We propose to conduct the largest seroepidemiologic study of prenatal exposures in schizophrenia to date, and the first to utilize a national birth cohort. The Finnish Maternity Cohort (FMC) consists of virtually all pregnancies in Finland from 1983 to the present; the total sample size is 1.5 million. Prenatal serum samples were obtained from each gravida, and the Finnish psychiatric registries contain diagnoses of schizophrenia on virtually all hospitalized and non-hospitalized cases. In the proposed Finnish Prenatal Study of Schizophrenia (FIPS-S), we propose to: 1) examine the relation between schizophrenia and several types of serologically documented prenatal infections, biomarkers of immune activation, thyroid hormone, and smoking; 2) assess interactive and mediating relationships between prenatal and perinatal risk factors for schizophrenia; 3) evaluate relationships between postnatal factors, including those during childhood and early adulthood, and prenatal exposures in the prediction of schizophrenia risk; 4) lay the groundwork for future gene-environment interaction studies of schizophrenia in this cohort. For this purpose, we shall use a nested case-control design. Cases (N=1,500) are defined as FMC cohort members who developed schizophrenia and schizoaffective disorder and the controls (N=1,500) represent unaffected offspring in the FMC matched to the cases on date of birth, ethnicity, birth place and residency in Finland at the time of first diagnosis of the case. Cases and matched controls will be identified by linkage between the FMC cohort and national Finnish psychiatric registries. Prenatal serum specimens will be assayed for serologically documented exposures in mothers of cases and controls. Record linkages with several additional national Finnish registries will be used to obtain standardized data on obstetric complications, childhood growth, and early adult premorbid intellectual function. Advantages of the study include: 1) the large sample size, and consequent high statistical power; 2) assessment of interactive and mediating effects with other risk factors; 3) virtually complete coverage of all births and hospitalizations for schizophrenia in Finland, which minimizes selection bias; and 4) homogeneity of the population, which minimizes confounding due to population stratification. Given that many of the exposures included in our studies are common in the population, this study has the potential to identify prenatal and other early developmental etiologies of schizophrenia, which may facilitate the eradication of a considerable portion of schizophrenia cases through preventive public health measures. This work also holds the promise of stimulating translational research aimed at identifying new pathogenic mechanisms for schizophrenia. Finally, the proposed investigation has the potential to lead to future studies on interactions between early developmental antecedents and susceptibility genes in the etiology of schizophrenia. PUBLIC HEALTH RELEVANCE: This work has high public health significance. The identification of prenatal etiologies of schizophrenia, and their interaction with other developmental antecedents, has the potential to lead to the eradication of a considerable portion of schizophrenia cases through public health measures, such as the administration of influenza vaccination, the prevention of sexually transmitted diseases, thyroid hormone supplementation, and anti-smoking campaigns targeted to pregnant women. Moreover, the research described in this proposal has future potential for the identification of susceptibility genes that interact with the prenatal exposures and other developmental antecedents in the etiology of schizophrenia.